title: [Studies on molecular mechanism of toxicity of anticancer drugs].
abstract: The clinical utility of anticancer drugs is seriously limited by the development of adverse effects and acquisition of resistance to these drugs by tumor cells. The mechanism underlying the toxicity of anticancer drugs is still not fully understood. To elucidate the mechanisms underlying the toxicity of anticancer drugs in greater detail, we performed a screen for determinants of sensitivity to adriamycin, an anthracycline antitumor antibiotic, using budding yeast as a model eukaryote. We found that overexpression of Akl1, a protein kinase of uncertain function, confers resistance to adriamycin. We investigated the function of Akl1 in adriamycin resistance and found that downregulation of the internalization step in endocytosis by Akl1 might be closely involved in the mechanism of adriamycin resistance. In human cells, overexpression of AAK1 and a human homologue of Akl1, also decreased adriamycin toxicity, suggesting that downregulation of endocytosis via phosphorylaiotn might be involved in the acquisition of adriamycin resistance not only in yeast cells but also in human cells. Further detailed investigation of the relationship between the endocytosis pathway and adriamycin toxicity might contribute further information for the improvement of chemotherapy with adriamycin.
authors.affiliation: Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University. ttsutomu@mail.pharm.tohoku.ac.jp
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Takahashi
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D004317:Doxorubicin / Q000633:toxicity; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004705:Endocytosis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; D004317:Doxorubicin; C451304:AAK1 protein, human; C486325:GAK protein, human; D017346:Protein Serine-Threonine Kinases